Anti-CGRP Antibody Formulation

ABSTRACT

Pharmaceutical formulations for anti-CGRP antibodies, and methods of using the same, are provided which are useful as treatment for migraines, episodic headaches, chronic headaches, chronic cluster headaches, and episodic cluster headaches.

The present invention is in the field of medicine. More specifically,the present invention relates to antibodies to calcitonin gene-relatedpeptide (CGRP) and pharmaceutical formulations thereof. Additionalaspects of the present invention relate to the use of such anti-CGRPantibodies and pharmaceutical formulations thereof for the treatment ofpatients suffering from CGRP-related disorders.

CGRP is a neuropeptide secreted by the nerves of the central andperipheral nervous systems and is implicated in pain pathways. The roleof CGRP in headache and migraine has been established in the art and anumber of clinical studies are currently evaluating the use of anti-CGRPantibodies for the treatment of headaches and migraine. (see, forexample, Dodick et al. Lancet Neurol; 13(9): 885-892 (2014)).

Liquid pharmaceutical formulations for antibodies intended for human userequire the chemical and physical stability of the antibody over itsextended shelf life (e.g. WO06083689 and in WO06096491). Chemicalinstability of the antibody can result from a number of chemicalreactions including deamidation, racemization, hydrolysis, oxidation,beta elimination and disulfide exchange. Physical instability can resultfrom processes such as denaturation, aggregation, precipitation, andadsorption to surfaces. Instability of the antibody can result in theformation of a polypeptide by-product or derivatives having lowactivity, increased toxicity, and/or increased immunogenicity, which canpose concerns about the safety and efficacy of the antibody.

While the possible occurrence of protein instabilities is widelyappreciated, it is difficult to predict particular instability issuesfor a particular protein. Applicants sought to formulate an anti-CGRPantibody (PCT/US2011/039381), wherein said antibody comprises a lightchain variable region (LCVR) and a heavy chain variable region (HCVR),wherein the amino acid sequence of said LCVR is SEQ ID NO: 1 and theamino acid sequence of said HCVR is SEQ ID NO: 2. In formulating theanti-CGRP antibody for use in therapy, applicants discovered severalfactors that contributed to the instability of the antibody, such asphoto degradation, polymer formation during freeze-thaw, and oxidationof polysorbate-80 (PS-80) in the formulation. Therefore, a stablepharmaceutical formulation was needed to overcome at least one or moreof the observed issues.

Accordingly, the present invention provides a pharmaceutical formulationcomprising an anti-CGRP antibody at a concentration of about 40 mg/mL toabout 160 mg/mL, histidine buffer at a concentration of about 5 mM toabout 20 mM, sodium chloride (NaCl) at a concentration of about 50 mM toabout 200mM, PS-80 at a concentration of about 0.03% (w/v) to about0.07% (w/v), and a pH at about 5.0 to about 6.5, wherein the anti-CGRPantibody comprises a light chain variable region (LCVR) and a heavychain variable region (HCVR), the amino acid sequence of LCVR given bySEQ ID NO: 1 and the amino acid sequence of HCVR given by SEQ ID NO: 2.Preferably, the pharmaceutical formulation comprises an anti-CGRPantibody with a light chain (LC) and a heavy chain (HC), the amino acidsequence of LC given by SEQ ID NO: 3 and the amino acid sequence of HCgiven by SEQ ID NO: 4. More preferably, the pharmaceutical formulationcomprises an anti-CGRP antibody with two LCs and two HCs, the amino acidsequence of each LC given by SEQ ID NO: 3 and the amino acid sequence ofeach HC given by SEQ ID NO: 4.

In an alternative embodiment, the present invention provides apharmaceutical formulation comprising an anti-CGRP antibody at aconcentration of about 50 mg/mL to about 150 mg/mL, histidine buffer ata concentration of about 5 mM to about 20 mM, sodium chloride at aconcentration of about 50 mM to about 200 mM, PS-80 at a concentrationof about 0.03% (w/v) to about 0.07% (w/v), and a pH at about 5.0 toabout 6.5, wherein the anti-CGRP antibody comprises a light chainvariable region (LCVR) and a heavy chain variable region (HCVR), theamino acid sequence of LCVR given by SEQ ID NO: 1 and the amino acidsequence of HCVR given by SEQ ID NO: 2. Preferably, the pharmaceuticalformulation comprises an anti-CGRP antibody with a light chain (LC) anda heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: 3and the amino acid sequence of HC given by SEQ ID NO: 4. Morepreferably, the pharmaceutical formulation comprises an anti-CGRPantibody with two LCs and two HCs, the amino acid sequence of each LCgiven by SEQ ID NO: 3 and the amino acid sequence of each HC given bySEQ ID NO: 4.

In an alternative embodiment, the present invention provides apharmaceutical formulation comprising an anti-CGRP antibody at aconcentration of about 100 mg/mL to about 160 mg/mL, histidine buffer ata concentration of about 5 mM to about 20 mM, NaCl at a concentration ofabout 50 mM to about 200 mM, PS-80 at a concentration of about 0.03%(w/v) to about 0.07% (w/v), and a pH at about 5.0 to about 6.5, whereinthe anti-CGRP antibody comprises a light chain variable region (LCVR)and a heavy chain variable region (HCVR), the amino acid sequence ofLCVR given by SEQ ID NO: 1 and the amino acid sequence of HCVR given bySEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises ananti-CGRP antibody with a light chain (LC) and a heavy chain (HC), theamino acid sequence of LC given by SEQ ID NO: 3 and the amino acidsequence of HC given by SEQ ID NO: 4. More preferably, thepharmaceutical formulation comprises an anti-CGRP antibody with two LCsand two HCs, the amino acid sequence of each LC given by SEQ ID NO: 3and the amino acid sequence of each HC given by SEQ ID NO: 4.

A further embodiment of the present invention also provides apharmaceutical formulation comprising an anti-CGRP antibody in ahistidine buffer, NaCl, and PS-80, wherein the concentration ofanti-CGRP antibody is selected from the group consisting of about 50mg/mL, about 100 mg/mL, about 120 mg/mL or about 150 mg/mL, histidinebuffer at a concentration of about 5 mM to about 20 mM, NaCl at aconcentration of about 50 mM to about 200 mM, PS-80 at a concentrationof about 0.03% (w/v) to about 0.07% (w/v), and a pH at about 5.0 toabout 6.5, wherein the anti-CGRP antibody comprises a light chainvariable region (LCVR) and a heavy chain variable region (HCVR), theamino acid sequence of LCVR given by SEQ ID NO: 1 and the amino acidsequence of HCVR given by SEQ ID NO: 2. Preferably, the pharmaceuticalformulation comprises an anti-CGRP antibody with a light chain (LC) anda heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: 3and the amino acid sequence of HC given by SEQ ID NO: 4. Morepreferably, the pharmaceutical formulation comprises an anti-CGRPantibody with two LCs and two HCs, the amino acid sequence of each LCgiven by SEQ ID NO: 3 and the amino acid sequence of each HC given bySEQ ID NO: 4.

Another embodiment of the present invention also provides apharmaceutical formulation comprising an anti-CGRP antibody in ahistidine buffer, NaCl, and PS-80, wherein the concentration ofanti-CGRP antibody is selected from the group consisting of about 50mg/mL, about 100 mg/mL, about 120 mg/mL or about 150 mg/mL, histidinebuffer at a concentration of about 10 mM, NaCl at a concentration ofabout 50 mM to about 200mM, PS-80 at a concentration of about 0.03%(w/v) to about 0.07% (w/v), and a pH at about 5.0 to about 6.5, whereinthe anti-CGRP antibody comprises a light chain variable region (LCVR)and a heavy chain variable region (HCVR), the amino acid sequence ofLCVR given by SEQ ID NO: 1 and the amino acid sequence of HCVR given bySEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises ananti-CGRP antibody with a light chain (LC) and a heavy chain (HC), theamino acid sequence of LC given by SEQ ID NO: 3 and the amino acidsequence of HC given by SEQ ID NO: 4. More preferably, thepharmaceutical formulation comprises an anti-CGRP antibody with two LCsand two HCs, the amino acid sequence of each LC given by SEQ ID NO: 3and the amino acid sequence of each HC given by SEQ ID NO: 4.

In another embodiment, the present invention also provides apharmaceutical formulation comprising an anti-CGRP antibody in ahistidine buffer, NaCl, and PS-80, wherein the concentration ofanti-CGRP antibody is selected from the group consisting of about 50mg/mL, about 100 mg/mL, about 120mg/m1 or about 150 mg/mL, histidinebuffer at a concentration of about 10 mM, NaCl at a concentration ofabout 150mM, PS-80 at a concentration of about 0.03% (w/v) to about0.07% (w/v), and a pH at about 5.0 to about 6.5, wherein the anti-CGRPantibody comprises a light chain variable region (LCVR) and a heavychain variable region (HCVR), the amino acid sequence of LCVR given bySEQ ID NO: 1 and the amino acid sequence of HCVR given by SEQ ID NO: 2.

Preferably, the pharmaceutical formulation comprises an anti-CGRPantibody with a light chain (LC) and a heavy chain (HC), the amino acidsequence of LC given by SEQ ID NO: 3 and the amino acid sequence of HCgiven by SEQ ID NO: 4. More preferably, the pharmaceutical formulationcomprises an anti-CGRP antibody with two LCs and two HCs, the amino acidsequence of each LC given by SEQ ID NO: 3 and the amino acid sequence ofeach HC given by SEQ ID NO: 4.

In another embodiment, the present invention also provides apharmaceutical formulation comprising an anti-CGRP antibody in ahistidine buffer, NaCl, and PS-80, wherein the concentration ofanti-CGRP antibody is selected from the group consisting of about 50mg/mL, about 100 mg/mL, about 120 mg/m1 or about 150 mg/mL, histidinebuffer at a concentration of about 10 mM, NaCl at a concentration ofabout 150 mM, PS-80 at a concentration of about 0.05% (w/v), and a pH atabout 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a lightchain variable region (LCVR) and a heavy chain variable region (HCVR),the amino acid sequence of LCVR given by SEQ ID NO: 1 and the amino acidsequence of HCVR given by SEQ ID NO: 2. Preferably, the pharmaceuticalformulation comprises an anti-CGRP antibody with a light chain (LC) anda heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: 3and the amino acid sequence of HC given by SEQ ID NO: 4. Morepreferably, the pharmaceutical formulation comprises an anti-CGRPantibody with two LCs and two HCs, the amino acid sequence of each LCgiven by SEQ ID NO: 3 and the amino acid sequence of each HC given bySEQ ID NO: 4.

More particularly, the present invention provides for a pharmaceuticalformulation comprising an anti-CGRP antibody at a concentration of about120 mg/mL, histidine buffer at a concentration of about 10 mM, NaCl at aconcentration of about 150 mM, PS-80 at a concentration of about 0.05%(w/v), and pH of about 5.8, wherein the anti-CGRP antibody comprises aLCVR and a HCVR, the amino acid sequence of LCVR given by SEQ ID NO: 1and the amino acid sequence of HCVR given by SEQ ID NO: 2. Preferably,the pharmaceutical formulation comprises an anti-CGRP antibody with alight chain (LC) and a heavy chain (HC), the amino acid sequence of LCgiven by SEQ ID NO: 3 and the amino acid sequence of HC given by SEQ IDNO: 4. More preferably, the pharmaceutical formulation comprises ananti-CGRP antibody with two LCs and two HCs, the amino acid sequence ofeach LC given by SEQ ID NO: 3 and the amino acid sequence of each HCgiven by SEQ ID NO: 4.

In a further embodiment, the present invention provides a pharmaceuticalformulation comprising an anti-CGRP antibody in a histidine buffer,wherein the concentration of the anti-CGRP antibody is about 40 mg/mL toabout 160 mg/mL. Preferably, the concentration of the anti-CGRP antibodyis about 50 mg/mL to about 150 mg/mL. More preferably, the concentrationof the anti-CGRP antibody is about 50 mg/mL, about 100 mg/mL, about 120mg/mL, or about 150 mg/mL. In particular embodiments the pharmaceuticalformulation comprises an anti-CGRP antibody at a concentration of about40 mg/mL to about 160 mg/mL in a histidine buffer, wherein the histidinebuffer is at a concentration of about 5 mM to about 20 mM. Preferably,the histidine buffer is at a concentration of about 10 mM.

In another embodiment, the present invention provides a pharmaceuticalformulation comprising an anti-CGRP antibody and NaCl, wherein theconcentration of NaCl is about 50 mM to about 200 mM. Preferably, theconcentration of NaCl is about 125 to about 175mM. More preferably, theconcentration of NaCl is about 150 mM. Even more preferably, thepharmaceutical formulation comprises an anti-CGRP antibody, histidinebuffer at 10 mM, and NaCl, wherein the concentration of NaCl is about 50mM to about 200 mM. Most preferably, the pharmaceutical formulationcomprises an anti-CGRP antibody at a concentration in the range of about40 mg/mL to about 160 mg/mL, histidine buffer at a concentration ofabout 10 mM, NaCl at a concentration of about 50 mM to about 200 mM, anda pH of about 5.8. Preferably, the NaCl is at a concentration of about150 mM.

In another embodiment, the present invention provides a pharmaceuticalformulation comprising an anti-CGRP antibody and PS-80, wherein theconcentration of PS-80 is about 0.03% (w/v) to about 0.07% (w/v).Preferably the concentration of PS-80 in the pharmaceutical formulationis about 0.05% (w/v). In a preferred embodiment, the pharmaceuticalformulation comprises an anti-CGRP antibody at a concentration in therange of about 40 mg/mL to about 160 mg/mL, and PS-80 at a concentrationof about 0.03% (w/v) to about 0.07% (w/v). More preferably, thepharmaceutical formulation comprises an anti-CGRP antibody at aconcentration in the range of about 40 mg/mL to about 160 mg/mL,histidine buffer at a concentration of about 5mM to 20mM, and of PS- 80is about 0.05% (w/v). Even more preferably, the pharmaceuticalformulation comprises an anti-CGRP antibody at a concentration in therange of about 40 mg/mL to about 160 mg/mL, NaCl at a concentration ofabout 50 mM to about 200 mM, and PS-80 at a concentration of about 0.05%(w/v). Most preferably, the pharmaceutical formulation comprises ananti-CGRP antibody at a concentration in the range of about 100 mg/mL toabout 150 mg/mL, histidine buffer at a concentration of about 125 mM toabout 175mM, PS-80 at a concentration of about 0.05% (w/v) and a pH ofabout 5.8. The present invention also provides a method of treating orpreventing a condition related to elevated levels of CGRP, preferablyheadaches and/or migraines comprising administering to a patient in needthereof a therapeutically effective amount of a pharmaceuticalformulation of the present invention. Some embodiments of the presentinvention provide a method of treating or preventing migraine, episodicheadache, chronic headache, chronic cluster headaches, and/or episodiccluster headaches comprising administering to a patient in need thereofa therapeutically effective amount of a pharmaceutical formulation ofthe present invention. According to some embodiments, a method oftreating or preventing chronic and episodic cluster headaches isprovided comprising administering to a patient in need thereof a dose of300 mg of an anti-CGRP antibody. Further embodiments provide a method oftreating or preventing chronic and episodic cluster headachesadministering to a patient in need thereof a dose of 360 mg of ananti-CGRP antibody. In other embodiments, the present invention providesa method of treating or preventing chronic and episodic migrainescomprising administering to a patient in need thereof a dose of 120 mgof an anti-CGRP antibody. Further embodiments provide a method oftreating or preventing chronic and episodic migraine comprisingadministering to a patient in need thereof a dose of 240 mg of ananti-CGRP antibody. Another embodiment provides a provide a method oftreating or preventing chronic and episodic migraine comprisingadministering to a patient in need thereof an initial loading dose of240 mg of an anti-CGRP antibody followed by a monthly maintenance doseof 120 mg of an anti-CGRP antibody. Preferably, the dose is administeredat weekly, semi-monthly, monthly or quarterly intervals. Morepreferably, the administration is monthly.

In another embodiment, the present invention also provides a method totreat or prevent cluster headache in a patient in need by administeringa monthly subcutaneous dose of 300mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody binds to an epitope comprising amino acidsVTHRLAGLLSR of SEQ ID NO: 7. In a further embodiment, the presentinvention provides a method to treat or prevent episodic migraine in apatient in need by administering a monthly subcutaneous dose of 120 mgof an anti-CGRP antibody, wherein the anti-CGRP antibody comprises aLCVR given by the amino acid sequence of SEQ ID NO: 1 and a HCVR givenby the amino acid of SEQ ID NO: 2. Preferably, the anti-CGRP antibody isin a pharmaceutical formulation comprising about 10 mM histidine buffer,about 150 mM NaCl, about 0.05% PS-80, and a pH of about 5.8. In anotherembodiment, the present invention also provides a method to treat orprevent cluster headache in a patient in need by administering a monthlysubcutaneous dose of 300 mg of an anti-CGRP antibody, wherein theanti-CGRP antibody comprises a LC given by the amino acid sequence ofSEQ ID NO: 3 and a HC given by the amino acid of SEQ ID NO: 4.Preferably, the anti-CGRP antibody is in a pharmaceutical formulationcomprising about 10mM histidine buffer, about 150 mM NaCl, about 0.05%PS-80 and a pH of about 5.8.

In another embodiment, the present invention also provides a method totreat or prevent cluster headache in a patient in need thereof byadministering a monthly dose of 300 mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody comprises a LCVR given by the amino acid sequenceof SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ ID NO: 2, andwherein the anti-CGRP antibody is in a pharmaceutical compositioncomprising a histidine buffer. In a particular embodiment, the anti-CGRPantibody is in a pharmaceutical composition comprising a histidinebuffer at a pH of about 5.5-6.1. In another particular embodiment, theanti-CGRP antibody is in a pharmaceutical composition comprising about 5mM to about 20 mM histidine buffer. Preferably the pharmaceuticalcomposition has a pH of about 5.7-6.0. More preferably, thepharmaceutical composition has a pH of about 5.8.

In another particular embodiment, the present invention also provides amethod to treat or prevent cluster headache in a patient in need thereofby administering a monthly dose of 300 mg of an anti-CGRP antibody,wherein the anti-CGRP antibody comprises a LCVR given by the amino acidsequence of SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ IDNO: 2, and wherein the anti-CGRP antibody is in a pharmaceuticalcomposition comprising a buffer, NaCl, and a surfactant. Preferably theanti-CGRP antibody is in a pharmaceutical composition comprising abuffer, about 50 mM to about 200 mM of NaCl, and a surfactant. Morepreferably, the anti-CGRP antibody is in a pharmaceutical composition ata pH of about 5.7-6.0. Most preferably, the anti-CGRP antibody is in apharmaceutical composition at a pH of about 5.8.

In another particular embodiment, the present invention also provides amethod to treat or prevent cluster headache in a patient in need thereofby administering a monthly dose of 300 mg of an anti-CGRP antibody,wherein the anti-CGRP antibody comprises a LCVR given by the amino acidsequence of SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ IDNO: 2, and wherein the anti-CGRP antibody is in a pharmaceuticalcomposition comprising a buffer, salt, and PS-80 as a surfactant.Preferably the anti-CGRP antibody is in a pharmaceutical compositioncomprising a buffer, salt, and about 0.03% (w/v) to about 0.07% (w/v)PS-80. More preferably, the anti-CGRP antibody is in a pharmaceuticalcomposition at a pH of about 5.7-6.0. Most preferably, the anti-CGRPantibody is in a pharmaceutical composition at a pH of about 5.8.

In a further embodiment, the present invention provides a method totreat or prevent episodic migraine in a patient in need by administeringa monthly subcutaneous dose of 120 mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody binds to an epitope comprising amino acidsVTHRLAGLLSR of SEQ ID NO: 7. In a further embodiment, the presentinvention provides a method to treat or prevent episodic migraine in apatient in need by administering a monthly subcutaneous dose of 120 mgof an anti-CGRP antibody, wherein the anti-CGRP antibody comprises aLCVR given by the amino acid sequence of SEQ ID NO: 1 and a HCVR givenby the amino acid of SEQ

ID NO: 2. Preferably, the anti-CGRP antibody is in a pharmaceuticalformulation comprising about 10 mM histidine buffer, about 150 mM NaCl,about 0.05% PS-80, and a pH of about 5.8. In a further embodiment, thepresent invention provides a method to treat or prevent episodicmigraine in a patient in need by administering a monthly subcutaneousdose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibodycomprises a LC given by the amino acid sequence of SEQ ID NO: 3 and a HCgiven by the amino acid of SEQ ID NO: 4. Preferably, the anti-CGRPantibody is in a pharmaceutical formulation comprising about 10 mMhistidine buffer, about 150 mM NaCl, about 0.05% PS-80 and a pH of about5.8. In another embodiment the present invention provides a method totreat or prevent episodic migraine in a patient in need thereof byadministering a monthly dose of 120 mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody comprises a LCVR given by the amino acid sequenceof SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ ID NO: 2, andwherein the anti-CGRP antibody is in a pharmaceutical compositioncomprising a histidine buffer. In a particular embodiment, the anti-CGRPantibody is in a pharmaceutical composition comprising a histidinebuffer at a pH of about 5.5-6.1. In another particular embodiment, theanti-CGRP antibody is in a pharmaceutical composition comprising about 5mM to about 20 mM histidine buffer. Preferably the pharmaceuticalcomposition has a pH of about 5.7-6.0. More preferably, thepharmaceutical composition has a pH of about 5.8.

In another particular embodiment, the present invention provides amethod to treat or prevent episodic migraine in a patient in needthereof by administering a monthly dose of 120 mg of an anti-CGRPantibody, wherein the anti-CGRP antibody comprises a LCVR given by theamino acid sequence of SEQ ID NO: 1 and a HCVR given by the amino acidof SEQ ID NO: 2, and wherein the anti-CGRP antibody is in apharmaceutical composition comprising a buffer, NaCl, and a surfactant.Preferably the anti-CGRP antibody is in a pharmaceutical compositioncomprising a buffer, about 50 mM to about 200 mM of NaCl, and asurfactant. More preferably, the anti-CGRP antibody is in apharmaceutical composition at a pH of about 5.7-6.0. Most preferably,the anti-CGRP antibody is in a pharmaceutical composition at a pH ofabout 5.8.

In another particular embodiment the present invention provides a methodto treat or prevent episodic migraine in a patient in need byadministering a monthly dose of 120 mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody comprises a LCVR given by the amino acid sequenceof SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ ID NO: 2, andwherein the anti-CGRP antibody is in a pharmaceutical compositioncomprising a buffer, salt and PS-80 as a surfactant. Preferably theanti-CGRP antibody is in a pharmaceutical composition comprising abuffer, salt, and about 0.03% (w/v) to about 0.07% (w/v) PS-80. Morepreferably, the anti-CGRP antibody is in a pharmaceutical composition ata pH of about 5.7-6.0. Most preferably, the anti-CGRP antibody is in apharmaceutical composition at a pH of about 5.8.

In another embodiment the present invention provides a method to treator prevent chronic migraine in a patient in need thereof byadministering a monthly dose of 120 mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody comprises a LCVR given by the amino acid sequenceof SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ ID NO: 2, andwherein the anti-CGRP antibody is in a pharmaceutical compositioncomprising a histidine buffer. In a particular embodiment, the anti-CGRPantibody is in a pharmaceutical composition comprising a histidinebuffer at a pH of about 5.5-6.1. In another particular embodiment, theanti-CGRP antibody is in a pharmaceutical composition comprising about 5mM to about 20 mM histidine buffer. Preferably the pharmaceuticalcomposition has a pH of about 5.7-6.0. More preferably, thepharmaceutical composition has a pH of about 5.8.

In another particular embodiment, the present invention provides amethod to treat or prevent chronic migraine in a patient in need byadministering a monthly dose of 120 mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody comprises a LCVR given by the amino acid sequenceof SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ ID NO: 2, andwherein the anti-CGRP antibody is in a pharmaceutical compositioncomprising a buffer, NaCl, and a surfactant. Preferably the anti-CGRPantibody is in a pharmaceutical composition comprising a buffer, about50 mM to about 200 mM of NaCl, and a surfactant. More preferably, theanti-CGRP antibody is in a pharmaceutical composition at a pH of about5.7-6.0. Most preferably, the anti-CGRP antibody is in a pharmaceuticalcomposition at a pH of about 5.8.

In another particular embodiment the present invention provides a methodto treat or prevent chronic migraine in a patient in need byadministering a monthly dose of 120 mg of an anti-CGRP antibody, whereinthe anti-CGRP antibody comprises a LCVR given by the amino acid sequenceof SEQ ID NO: 1 and a HCVR given by the amino acid of SEQ ID NO: 2, andwherein the anti-CGRP antibody is in a pharmaceutical compositioncomprising a buffer, salt and PS-80 as a surfactant. Preferably theanti-CGRP antibody is in a pharmaceutical composition comprising abuffer, salt, and about 0.03% (w/v) to about 0.07% (w/v) PS-80. Morepreferably, the anti-CGRP antibody is in a pharmaceutical composition ata pH of about 5.7-6.0. Most preferably, the anti-CGRP antibody is in apharmaceutical composition at a pH of about 5.8.The present inventionalso provides a pharmaceutical formulation for use in therapy,preferably for use in the treatment or prevention of migraines and/orheadaches. In particular embodiments, the present invention provides apharmaceutical formulation for use in the treatment or prevention of atleast one or more of the following conditions: episodic migraine,chronic migraine, episodic headaches, chronic headaches, chronic clusterheadaches, and/or episodic cluster headaches. Preferably, the dose ofanti-CGRP antibody that is administered to a patient is 120 mg or 240 mgfor episodic and/or chronic migraine and 300 mg or 360 mg for episodicand/or chronic cluster headaches. Moreover, the present inventionprovides for a use of a pharmaceutical formulation of the presentinvention in the manufacture of a medicament for the treatment orprevention of migraine and/or headache. In particular, the presentinvention provides for a use of a pharmaceutical formulation in themanufacture of a medicament for the treatment of at least one of more ofthe following conditions: episodic migraine, chronic migraine, episodicheadache, chronic headache, chronic cluster headache, and/or episodiccluster headache.

As used herein, the term “patient” refers to a human In someembodiments, a patient is a human who has been diagnosed as having acondition or disorder for which treatment or administration with apharmaceutical formulation of the present invention is indicated. Insome embodiments, a patient is a human that is characterized as being atrisk of a condition or disorder for which treatment or administrationwith a pharmaceutical formulation of the present invention is indicated.

As used herein, the term “treating” (or “treat” or “treatment”) refersto processes involving a slowing, interrupting, arresting, controlling,stopping, reducing, or reversing the progression or severity of asymptom, disorder, condition, or disease, but does not necessarilyinvolve a total elimination of all disease-related symptoms, conditions,or disorders associated with CGRP activity. As used herein, the term“prevention” (or “prevent” or “preventing”) refers to precluding,averting, obviating, forestalling, reducing the incidence of, stopping,or hindering the symptoms of a disease, disorder and/or condition.Prevention includes administration to a subject who does not exhibitsymptoms of a disease, disorder, and/or condition at the time ofadministration.

As used herein, the term “therapeutically effective amount” refers tothe amount or dose of an anti-CGRP antibody in a pharmaceuticalformulation of the present invention, which upon single or multiple doseadministration to the patient, provides the desired pharmacologicaleffect in the patient. A dose can include a higher initial loading dose,followed by a lower dose. A “dose” refers to a predetermined quantity ofa therapeutic drug calculated to produce the desired therapeutic effectin a patient. A therapeutically effective amount can be determined bythe attending diagnostician, as one skilled in the art, by considering anumber of factors such as the patient's size, age, and general health,the specific disease or surgical procedure involved, the degree orseverity of the disease or malady, the response of the individualpatient, the mode of administration, the bioavailability characteristicsof the preparation administered, the dose regimen selected, and the useof any concomitant medications.

As used herein, the term “month” or derivations thereof, refers to atime period that includes 28 to 31 consecutive days. The term “about” asused herein, means in reasonable vicinity of the stated numerical value,such as plus or minus 10% of the stated numerical value.

The general structure of an “antibody” is known in the art. Anti-CGRPantibodies are disclosed in WO2011/156324. As used herein, a “drugsubstance” (“DS”) is a formulation that comprises an antibody, buffer(e.g. histidine), excipient (e.g. NaCl), and surfactant (e.g. PS-80),and is within a certain pH range or at a specified pH. A “drug product”(“DP”) is a formulation comprising a buffer, excipient, surfactant, andantibody, wherein the antibody in the DP may be at a lower concentrationthan the antibody concentration in the DS.

The pharmaceutical formulations of the present invention are in theliquid dosage form of a solution. Administration of the pharmaceuticalformulations of the present invention may be via parenteraladministration. Parenteral administration, as used herein, may includeinjection of a dosage form into the body by a sterile syringe or someother mechanical device such as an infusion pump. Parenteral routes caninclude intravenous, intramuscular, subcutaneous, and intraperitonealroutes of administration. Subcutaneous administration is a preferredroute. The pharmaceutical formulations of the present invention areintended for pharmaceutical use in a human.

The invention is further illustrated by the following examples whichshould not be construed as limiting.

EXAMPLES

Production of Antibodies

Antibodies of the invention can be made and purified as follows. Anappropriate host cell, such as CHO, is either transiently or stablytransfected with an expression system for secreting antibodies using anoptimal predetermined HC:LC vector ratio or a single vector systemencoding both LC and both HC, such as each LC being SEQ ID NO: 3 andeach HC being SEQ ID NO: 4. Clarified media, into which the antibody hasbeen secreted, is purified using any of many commonly-used techniques.For example, the medium may be conveniently applied to a Protein A or GSepharose FF column that has been equilibrated with a compatible buffer,such as phosphate buffered saline (pH 7.4). The column is washed toremove nonspecific binding components. The bound antibody is eluted, forexample, by pH gradient. Antibody fractions are detected, such as bySDS-PAGE, and then are pooled. Further purification is optional,depending on the intended use. The antibody may be concentrated and/orsterile filtered using common techniques. Soluble aggregate andmultimers may be effectively removed by common techniques, includingsize exclusion, hydrophobic interaction, ion exchange, or hydroxyapatitechromatography. The purity of the antibody after these chromatographysteps is greater than 99%. The product may be immediately frozen at −70°C. in the formulation matrix of the invention or may be lyophilized. Theamino acid and nucleic acid sequences for the exemplified antibody areprovided below.

Manufacture of an anti-CGRP Pharmaceutical Formulation

The manufacturing process for an anti-CGRP antibody pharmaceuticalformulation of the present invention includes compounding of the bufferexcipient composition, and adding the anti-CGRP antibody drug substance(DS).

The buffer excipient composition consists of L-Histidine, L-HistidineHydrochloride Monohydrate, NaCl , PS-80, and water (Table 1). Theanti-CGRP antibody comprises a light chain of SEQ ID NO: 3, and a heavychain of SEQ ID NO: 4.

TABLE 1 Buffer excipient composition Quantity Final Component (mg/mL)Concentration L-Histidine 0.478  10 mM L-Histidine 1.45 HydrochlorideMonohydrate NaCl 8.76 150 mM PS-80 0.50 0.05% (w/v)* Water for Injectionq.s. to 1 mL *weight per volume

The buffer excipient composition is prepared and filtered. Anappropriate quantity of water at a temperature not more than 25° C. isweighed into a tared empty vessel of appropriate size. The appropriatequantities of L-Histidine, L-Histidine Hydrochloride Monohydrate andNaCl are added and mixed. PS-80 is weighed out in a glass container andan appropriate quantity of water is added into the glass container togive the indicated final concentration, and the solution is mixed. ThePS-80 solution is added to the other excipients, the solution is mixed,and the solution is prepared to have a pH and osmolality adjusted towithin 5.8±0.3 and 254-344 mOsm/Kg, respectively. The buffer excipientcomposition is passed through a filter for bioburden reduction.

The anti-CGRP antibody DS is prepared by expressing the antibody incells, purifying, concentrating, and freezing the antibody in solutionin 10 mM histidine buffer, 150 mM NaCl, 0.05% PS-80, and pH of about5.8. The DS solution is stored at −70° C. The frozen DS is equilibratedto a temperature of 20±5° C. and mixed with an appropriate amount of thebuffer excipient solution to achieve the intermediate antibody DPconcentration. The pH of the solution is checked to be within 5.8±0.3.

The solution is mixed and a sample is taken for an in-process UV assayto determine the antibody DP concentration. An appropriate quantity ofthe buffer excipient solution is added to reach the final target batchweight. After mixing, the pH of the solution is checked to be within5.8±0.3. The antibody DP solution is passed through a filter forbioburden reduction prior to sterile filtration and filling into vialsor syringes.

The final concentration of the antibody DP can be between about 40 mg/mLto about 160 mg/mL.

Photo Stability

Light can influence the active molecule in a drug formulation, as wellas the final product or package resulting in photodegradation that mayresult in the loss of potency of the product. The effect of light onanti-CGRP antibody formulated in citrate buffer or histidine buffer atpH 5.8 in glass prefilled syringes is evaluated by size exclusionchromatography (SEC). The light exposure levels are approximately 20% ofICH Q1B for visible light and 10% for the UV light.

Anti-CGRP antibody, at approximately 165 mg/mL (in 10 mM Histidine, 150mM NaCl, pH 6.0), is divided into two aliquots. One aliquot is dialyzedinto 10 mM histidine, 150mM NaCl, pH 5.8 buffer, and the other aliquotis dialyzed into 10 mM citrate, 150 mM NaCl, pH 5.8 buffer. Followingdialysis, the antibody is diluted with the appropriate buffer (histidineor citrate) to 50 mg/mL or to 120 mg/mL. PS-80 is added to eachformulation to a final concentration of 0.05%. The formulations arefiltered through a 0.22 um sterilizing grade PVDF filter and filled intoglass prefilled syringes. Eight syringes per formulation for sizeexclusion chromatography (SEC) analysis are utilized. Syringes areplaced in light chambers for exposure to either ultraviolet (UV),visible or both UV and visible light. Syringes in an opaque box are alsoincluded as “dark” controls. The temperature is constant at 20° C. Totalpolymer is measured by SEC. The results are summarized in Table 2.

TABLE 2 Comparison of percent total polymer between histidine andcitrate buffer DP Concentration and Histidine Buffer Citrate BufferLight Condition Total Polymer (%) Total Polymer (%)  50 mg/mL Dark 1.441.70  50 mg/mL UV 1.63 2.06  50 mg/mL VIS 1.88 2.60  50 mg/mL UV/ VIS2.33 3.47 120 mg/mL Dark 1.54 1.98 120 mg/mL UV 2.18 2.89 120 mg/mL VIS2.38 3.66 120 mg/mL UV/ VIS 2.86 4.20

Under conditions essentially as described above, the results provided inTable 2 demonstrate that the percent total polymer in histidine bufferwere lower than that observed with citrate buffer. These datademonstrate that the formulations comprising the histidine bufferprovide for better stability following exposure to light compared toformulations comprising citrate.

Excipient Compatibility Study

Stability of anti-CGRP antibody pharmaceutical formulations is evaluatedin an excipient compatibility study. The formulations, at pH 6.0,comprise 120 mg/mL anti-CGRP antibody, 0.04% PS-80, either 10mM or 20mMhistidine buffer, and either 150 mM NaCl, 5% mannitol, or a combinationof 100 mM NaCl and 1.5% mannitol. Formulations are prepared by dialysis,and stored in HDPE containers at indicated temperatures, and areprotected from light. Total polymer is determined by SEC at thebeginning of the study, at 1 month, and at 2 months.

TABLE 3 Comparison of percent total polymer between mannitol, NaCl, anda combination of mannitol and NaCl. Time Total Total Total pointsPolymer Polymer Polymer Formulation (months) (%), 5° C. (%), 25° C. (%),40° C. 10 mM Histidine, 0 1.53 1.53 1.53 150 mM NaCl 1 1.68 2.02 2.43 21.74 2.30 3.13 20 mM Histidine, 0 1.98 1.98 1.98 5% Mannitol 1 2.09 2.372.60 2 2.17 2.71 3.22 10 mM Histidine, 0 1.44 1.44 1.44 100 mM NaCl, 11.59 1.74 2.11 1.5%Mannitol 2 1.56 2.09 2.84

Under conditions essentially as described above, the percent totalpolymer in the formulation comprising 5% mannitol was higher compared tothe percent total polymer for the formulation comprising 150 mM NaCl, orthe formulation comprising 100 mM NaCl and 1.5% mannitol. The additionof NaCl and/or a combination of NaCl and mannitol is shown to positivelyaffect the stability of the protein.

Stability Following Freeze-Thaw

Freezing is a common processing step used to maintain stability andquality of a protein during development and production, and may allowfor a longer shelf life. However, freezing can induce complex physicaland chemical changes in the solvent/solute conditions, resulting indenaturation of proteins with the possibility of generation ofaggregates over time. The stability of pharmaceutical formulations inhistidine buffer following freeze-thaw (FT) is determined by SEC. Eightdifferent formulations are prepared and stored in HDPE containers. Eachformulation is at pH 6.0, comprises 0.02% PS-80,10mM histidine, andeither 150, 120, 100, or 20 mg/mL anti-CGRP antibody DP, and either 5%mannitol, 150 mM NaCl, or 1.5% mannitol and 100 mM NaCl.

Respective formulations in HDPE containers undergo three freeze-thawcycles. For one cycle, each formulation is frozen at −70° C. and thawedat room temperature. Respective formulations in HDPE containers undergoa slow freeze-thaw in a lyophilizer chamber. Controls are stored at 5°C. for the duration of the study. Following the third cycle or followingthe slow freeze-thaw, percent total polymer is assessed by SEC.

TABLE 4 Comparison of percent total polymer between mannitol, NaCl, anda combination of mannitol and NaCl. Total Polymer (%) 5% Mannitol 150 mMNaCl 1.5% Mannitol, 100 mM NaCl 120 mg/ml 20 mg/ml 150 mg/mL 100 mg/mL20 mg/mL 150 mg/mL 100 mg/mL 20 mg/mL Stress DP DP DP DP DP DP DP DPControl 1.7 2.2 1.64 1.65 1.19 1.45 1.6 1.2 FT cycle 1 1.8 2.8 1.58 1.651.71 1.57 1.51 1.28 FT cycle 2 N.D. N.D. 1.62 1.66 2.32 1.54 1.51 1.33FT cycle 3 1.8 5.1 1.6 1.61 3.15 1.51 1.5 1.29 Slow FT 1.9 11.6  1.721.71 1.91 1.52 1.48 N.D. N.D.: Not determined

Under conditions described above, the percent total polymer in theformulation comprising 5% mannitol and 20 mg/mL DP was increased in FTcycle 3 and in the slow FT, compared to the percent total polymer in allother formulations. The percent polymer was also increased in theformulation comprising 20 mg/mL DP and 150 mM NaCl. NaCl and/or acombination of NaCl and mannitol, together with concentrations ofantibody greater than 20 mg/mL in the formulation are shown to have astabilizing effect on the protein following freeze-thaw.

Capillary Shear Device

The capillary shear device (CSD) is a high shear force simulating stressdevice that uses a peristaltic pump and a capillary tube to studyphysical stress on a formulated DP. A CSD is used to evaluate shearforce physical stress of pharmaceutical formulations of the presentinvention, wherein said formulations comprise 10 mM histidine, 150 mMNaCl, anti-CGRP antibody at a concentration of 5 mg/mL, 40 mg/mL, or 120mg/mL, varying concentrations of PS-80, and pH of 6.0.

Anti-CGRP antibody DP is pumped through a 0.5mm inner diameter stainlesssteel capillary tube, with or without air, at a rate of approximately3.3 mL/sec using a peristaltic pump. This pump rate results in a shearvalue of approximately 105 sec⁻¹. Calculated energy dissipation isapproximately 105 W/Kg. Controls do not undergo pumping.

Three different capillary shear device set-ups are utilized in thisstudy. Stainless steel and PTFE capillary tubes are chosen because thesematerials are commonly used in manufacturing. Stainless steel capillarytubes without air in the system or PTFE capillary tubes without air inthe system both represent a nominal stress condition. Nominal stresswill be encountered when the solution is pumped using a peristaltic pumpthrough a filling needle. Stainless steel capillary tubes with airentrapment in the system represent a high stress condition because theprotein can unfold relatively easy in the air-liquid interface. Totalpolymer is determined by SEC, and particulate matter is determined byhigh accuracy particle counter (HIAC). SEC data are shown in Table 5,and HIAC data are shown in Table 6.

TABLE 5 Percent Total Polymer - SEC Stainless Stainless Steel % PS-80Control Steel with Air 5 mg/ml Antibody 0 0.89 0.91 1.65 0.005 1.04 1.031.63 0.02 1.06 1.06 1.13 0.03 1.09 1.06 1.12 0.05 1.17 1.19 1.23 40mg/ml Antibody 0 1.23 1.23 2.49 0.005 1.24 1.24 1.35 0.02 1.30 1.25 1.470.03 1.31 1.30 1.52 0.05 1.31 1.38 1.50 120 mg/ml Antibody 0 1.58 1.611.86 0.005 1.48 1.66 1.66 0.02 1.48 1.68 1.68 0.03 1.49 1.65 1.59 0.051.51 1.75 1.65

TABLE 6 Particulate Matter - HIAC 40 mg/mL anti-CGRP Antibody ParticleParticle Particle Particle Size Size Size % PS-80 Tubing Type (2 μm) (5μm) (10 μm) (25 μm) 0 Control 296 104 21 4 0.005 Control 53 26 11 6 0.02Control 53 21 8 0 0.03 Control 57 19 6 1 0.05 Control 78 24 5 0 0Stainless Steel 20284 1882 201 3 0.005 Stainless Steel 2612 501 94 40.02 Stainless Steel 1660 401 79 4 0.03 Stainless Steel 501 144 37 20.05 Stainless Steel 650 178 47 0 0 Stainless Steel w/Air 62009 4533024688 3683 0.005 Stainless Steel w/Air 1225 344 162 2 0.02 StainlessSteel w/Air 2993 803 178 4 0.03 Stainless Steel w/Air 3959 946 135 00.05 Stainless Steel w/Air 972 285 73 4

The SEC data in Table 5 show that under conditions essentially describedabove, the addition of PS-80 to the stainless steel with air groups(high stress conditions) led to a reduction in the total polymer.

Compared to formulations lacking PS-80, the addition of 0.005%, 0.02%,0.03%, or 0.05% of PS-80 led to a reduction in particle formation inmost of the groups as determined by HIAC (Table 6). These studiesdemonstrate that the addition of PS-80 to the solution reduces theparticulate matter present in the anti-CGRP antibody formulation.

PS-80 Oxidation

Formulations at pH 6.0 comprising the anti-CGRP antibody (120 mg/ml),10mM histidine, 150 mM NaCl, and 0.05% PS-80 are used to determine PS-80oxidation at various temperatures and time-points. Respectiveformulations are filled into vials or glass prefilled syringes andplaced in chambers at room temperature (at the beginning of the study),5° C., 25° C., or 40° C. The corresponding buffer (10 mM histidine, 150mM

NaCl, 0.05% PS-80, pH 6.0) without the antibody is used as a control.PS-80 hydrolysis method is used to determine percent PS-80. Amount offree oleic acid and amount of total oleic acid are determined. PS-80hydrolysis results in total oleic acid (TOA), and TOA is measured byhigh-performance liquid chromatography (HPLC). To obtain the percent ofintact PS-80, free oleic acid is subtracted from the total oleic acid.

TABLE 7 Percent PS-80 in formulations at various time-points andtemperatures Time Control DP PS-80% (months) Temperature (%) (%) 14 mLVial 0 RT 0.051 0.052 1 5° C. 0.052 0.05 25° C. 0.054 0.051 40° C. 0.0510.052 3 5 C. 0.052 0.052 25 C. 0.054 0.051 6 5 C. 0.054 0.051 25 C.0.047 0.05 2.25 mL 1 5 C. 0.051 0.05 Syringe 25 C. 0.048 0.051 40 C.0.029 0.05 3 5 C. 0.052 0.051 25 C. 0.008 0.05 6 5 C. 0.052 0.05 25 C.0.006 0.038

Following a procedure essentially as described above, oxidation of PS-80was most pronounced in the 2.25 mL control groups at 25° C. at 3 and 6months (Table 7). Oxidation of PS-80 was confirmed by mass spectrometry(data not shown).

In a similar study, formulations are prepared as indicated in FIG. 1. DSis dialyzed into the respective matrix and PS-80 is added or diluted toachieve the indicated final concentration. Respective formulations arefilled into glass prefilled syringes and stored in chambers at roomtemperature, 5° C., 25° C., 30° C., or 40° C. The concentration of PS-80is determined at the beginning of the study at room temperature, after1, 2, or 3 months at 5° C., 25° C., or 30° C., and at 6 months at 5° C.or 25° C. The results are shown in FIG. 1.

Following a procedure as essentially described above, oxidation of PS-80was observed in formulations comprising 5 mg/mL antibody. These datashow that antibody at a concentration greater than 5 mg/mL preventsoxidation of PS-80.

Dose Ranging Clinical Trial for Migraine

A phase IIb, randomized, double-blind, placebo-controlled, dose-rangingstudy was conducted with 410 patients aged 18-65 years with 4 to 14migraine headache days and at least 2 migraine attacks per month. Thepatients were randomly assigned (2:1:1:1:1) to placebo or 1 of 4LY2951742 dose groups. Subcutaneous injections of LY2951742 doses of 5mg, 50 mg, 120 mg, 300 mg or placebo were given once every 28 days for12 weeks. The primary objective was to assess whether at least one doseof LY2951742 was superior to placebo in the prevention of migraineheadache. Superiority was defined as a >95% posterior probability ofgreater improvement for any LY2951742 dose compared with placebo, asmeasured by the mean change from baseline in the number of migraineheadache days in the last 28-day period of the 12-week treatment phase.

The results showed that all 4 dose arms were numerically superior toplacebo on primary outcome measures at all-time points. One dose arm(120 mg) of LY2951742 met the primary objective (p=0.004) with asignificantly greater reduction compared to placebo in the number ofmigraine headache days in the last 28 day period of the 12 weektreatment phase.

Clinical Trial for Episodic Cluster Headache

A Phase III, randomized, double blind clinical trial is being conductedwith 162 patients aged 18-65 years with at least two cluster periodslasting from 7 days to 1 year (when untreated) and separated bypain-free remission periods of >1 month. The patients are randomlyassigned to either the placebo or treatment group. Subcutaneousinjections of a pharmaceutical composition comprising LY2951742 at dosesof 300 mg or placebo are given once every 30 days for 8 weeks. Theprimary objective is to assess whether 300 mg of LY2951742 was superiorto placebo in the prevention of episodic cluster headaches. The primaryoutcome measured is the mean change from baseline in number of weeklycluster headache attacks after treatment.

Sequences Exemplified LCVR (of an anti-CGRPantibody of the present invention) SEQ ID NO: 1DIQMTQSPSSLSASVGDRVTITCRASKDISKYLNW YQQKPGKAPKLLIYYTSGYHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGDALPPTFGGGTKVE IK Exemplified HCVR (of an anti-CGRPantibody of the present invention) SEQ ID NO: 2QVQLVQSGAEVKKPGSSVKVSCKASGYTFGNYWMQ WVRQAPGQGLEWMGAIYEGTGKTVYIQKFADRVTITADKSTSTAYMELSSLRSEDTAVYYCARLSDYVSG FGYWGQGTTVTVSSExemplified LC (of an anti-CGRP antibody of the present invention)SEQ ID NO: 3 DIQMTQSPSSLSASVGDRVTITCRASKDISKYLNWYQQKPGKAPKLLIYYTSGYHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQGDALPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC Exemplified HC (of an anti-CGRPantibody of the present invention) SEQ ID NO: 4QVQLVQSGAEVKKPGSSVKVSCKASGYTFGNYWMQ WVRQAPGQGLEWMGAIYEGTGKTVYIQKFADRVTITADKSTSTAYMELSSLRSEDTAVYYCARLSDYVSG FGYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG Exemplified nucleotide sequence(encoding a LC of an anti-CGRP antibody of the present invention)SEQ ID NO: 5 gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgcc gagcaagtaaagacatttctaagtatttaaactggtatcagcagaaaccagggaaagcccctaagctcct gatctattacacatcaggatatcactcaggagtcccatcaaggttcagtggcagtggatctgggacagat ttcactctcaccatcagcagtctgcaacctgaagattttgcaacttactactgtcaacaaggtgatgcgc ttcctccgacgttcggcggagggaccaaggtggagatcaaacggactgtggctgcaccatctgtcttcat cttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctat cccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtca cagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacga gaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaac aggggagagtgcExemplified nucleotide sequence (encoding a HC of an anti-CGRPantibody of the present invention) SEQ ID NO: 6caggtgcagctggtgcagtctggggctgaggtgaa gaagcctgggtcctcagtgaaggtttcctgcaaggcatctggctacacctttggtaattactggatgcag tgggtgcgacaggcccctggacaagggcttgagtggatgggagctatttatgagggaactggtaagactg tgtacattcagaagttcgccgacagagtcaccattaccgcggacaaatccacgagcacagcctacatgga gctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagattaagtgattacgtctcggga tttggctactggggccaaggaaccacggtcaccgtctcctcagcctccaccaagggcccatcggtcttcc cgctagcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactactt ccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtc ctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaaga cctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatgg tcccccatgcccaccctgcccagcacctgaggccgccgggggaccatcagtcttcctgttccccccaaaa cccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaag accccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcggga ggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggc aaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagcca aagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggt cagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggaaagcaatgggcag ccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggc taaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacacagaagagcctctccctgtctctgggttga Human αCGRP Peptide SEQ ID NO: 7ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGS KAF

1-41. (cancelled)
 42. A method of treating or preventing migraines,episodic headaches, chronic headaches, chronic cluster headaches, orepisodic cluster headaches comprising administering to a patient atherapeutically effective amount of a pharmaceutical formulationcomprising an anti-CGRP antibody at a concentration of about 40 mg/mL toabout 160 mg/mL, histidine buffer at a concentration of about 5 mM toabout 20 mM, NaCl at a concentration of about 50 mM to about 200mM,PS-80 at a concentration of about 0.03% (w/v) to about 0.07% (w/v), anda pH at about 5.0 to about 6.5, wherein the anti-CGRP antibody comprisesa light chain variable region (LCVR) and a heavy chain variable region(HCVR), the amino acid sequence of LCVR given by SEQ ID NO: 1 and theamino acid sequence of HCVR given by SEQ ID NO:
 2. 43. The method ofclaim 42, wherein the dose of anti-CGRP antibody administered to apatient is about 300 mg.
 44. The method of claim 42, wherein the dose ofanti-CGRP antibody administered to a patient is about 240 mg.
 45. Themethod of claim 42, wherein the dose of anti-CGRP antibody administeredto a patient is about 120 mg.
 46. The method of claim 44, wherein the240 mg dose is followed by a monthly maintenance dose of 120 mg.
 47. Themethod according to claim 43, wherein the dose is administered atweekly, semi-monthly or monthly intervals.
 48. The method according toclaim 44, wherein the dose is administered at weekly, semi-monthly ormonthly intervals.
 49. The method according to claim 45, wherein thedose is administered at weekly, semi-monthly or monthly intervals.
 50. Amethod to treat or prevent episodic or chronic migraine in a patientcomprising administering a monthly subcutaneous dose of 120 mg of ananti-CGRP antibody, wherein the anti-CGRP antibody comprises a LC givenby the amino acid sequence of SEQ ID NO: 3 and a HC given by the aminoacid of SEQ ID NO:
 4. 51. A method to treat or prevent episodic orchronic migraine in a patient comprising administering a monthlysubcutaneous dose of 240 mg of an anti-CGRP antibody, wherein theanti-CGRP antibody comprises a LC given by the amino acid sequence ofSEQ ID NO: 3 and a HC given by the amino acid of SEQ ID NO:
 4. 52. Amethod to treat or prevent episodic or chronic migraine in a patientcomprising administering a monthly subcutaneous dose of 240 mg of ananti-CGRP antibody followed by a monthly maintenance dose of 120 mg ofthe anti-CGRP antibody, wherein the anti-CGRP antibody comprises a LCgiven by the amino acid sequence of SEQ ID NO: 3 and a HC given by theamino acid of SEQ ID NO:
 4. 53. A method to treat or prevent clusterheadache in a patient comprising administering a monthly subcutaneousdose of 300 mg of an anti-CGRP antibody, wherein the anti-CGRP antibodycomprises a LC given by the amino acid sequence of SEQ ID NO: 3 and a HCgiven by the amino acid of SEQ ID NO:
 4. 54. The method according toclaim 50, wherein the anti-CGRP antibody is in a pharmaceuticalformulation comprising a histidine buffer.
 55. The method according toclaim 51, wherein the anti-CGRP antibody is in a pharmaceuticalformulation comprising a histidine buffer.
 56. The method according toclaim 52, wherein the anti-CGRP antibody is in a pharmaceuticalformulation comprising a histidine buffer.
 57. The method according toclaim 53, wherein the anti-CGRP antibody is in a pharmaceuticalformulation comprising a histidine buffer.
 58. The method according toclaim 54, wherein the histidine buffer is at a concentration of about 10mM to about 15 mM.
 59. The method according to claim 55, wherein thehistidine buffer is at a concentration of about 10 mM to about 15 mM.60. The method according to claim 56, wherein the histidine buffer is ata concentration of about 10 mM to about 15 mM.
 61. The method accordingto claim 57, wherein the histidine buffer is at a concentration of about10 mM to about 15 mM.
 62. The method according to claim 58, wherein theanti-CGRP antibody is in a pharmaceutical formulation at a pH of about5.7-6.0.
 63. The method according to claim 59, wherein the anti-CGRPantibody is in a pharmaceutical formulation at a pH of about 5.7-6.0.64. The method according to claim 60, wherein the anti-CGRP antibody isin a pharmaceutical formulation at a pH of about 5.7-6.0.
 65. The methodaccording to claim 61, wherein the anti-CGRP antibody is in apharmaceutical formulation at a pH of about 5.7-6.0.
 66. The methodaccording to claim 62, wherein the pharmaceutical formulation has a pHof about 5.8.
 67. The method according to claim 63, wherein thepharmaceutical formulation has a pH of about 5.8.
 68. The methodaccording to claim 64, wherein the pharmaceutical formulation has a pHof about 5.8.
 69. The method according to claim 65, wherein thepharmaceutical formulation has a pH of about 5.8.
 70. The methodaccording to claim 50, wherein the anti-CGRP antibody is in apharmaceutical formulation comprising about 10mM histidine buffer, about150mM NaCl, about 0.05% PS-80, and has a pH of about 5.8.
 71. The methodaccording to claim 51, wherein the anti-CGRP antibody is in apharmaceutical formulation comprising about 10 mM histidine buffer,about 150 mM NaCl, about 0.05% PS-80, and has a pH of about 5.8.
 72. Themethod according to claim 52, wherein the anti-CGRP antibody is in apharmaceutical formulation comprising about 10 mM histidine buffer,about 150 mM NaC1, about 0.05% PS-80, and has a pH of about 5.8.
 73. Themethod according to claim 53, wherein the anti-CGRP antibody is in apharmaceutical formulation comprising about 10 mM histidine buffer,about 150 mM NaC1, about 0.05% PS-80, and has a pH of about 5.8.